Prostaglandins (PGs) which belong to the prostanoids family are known to have diverse biological activities such as contraction and relaxation of smooth muscle, inhibition and enhancement of neurotransmitter release, inflammation, including pain and bone metabolism (Coleman et al. 1989; EP1114816).
In particular, Prostaglandin E2 (PGE2) which is the naturally-occurring agonist of EP receptor, was found to have various roles in ovulation and fertilization, in the control of blood pressure, febrile responses, regulation of bicarbonate secretion induced by acid-stimulation in the duodenum, bone resorption, smooth muscle contraction regulation, TNF down-regulation and inhibition of microglial IL-12 secretion (Ushikubi et al., 2000; Miyaura. et al., 2001, Nippon Yakunigaku Zasshi, 117(4): 293-7; Benoit et al., 2002 and Levi et al., 1998 Biochimie 80(11):899-904).
The EP receptor has been further classified into four different receptor sub-types: EP1, EP2, EP3, and EP4 (Coleman et al. 1994).
Knock-out mice lacking each sub-type of the EP receptor gave evidence of the different roles played by these receptors (Ushikubi et al., 2000) in various mechanisms. The EP receptors are for example involved in mechanisms such as ovulation (EP2), blood pressure control (EP2), closure of ductus arteriosus (EP4), bone resorption (EP4) (Miyaura et al., 2001), erectile dysfunction (EP4) and anti-inflammatory activity (EP4) (Takayama et al., 2002).
Renal Prostaglandin E2 (PGE2) is crucial for normal renal function by dilating the glomerular microcirculation and vasa recta, applying the renal medulla and modulating salt and water transport in the distal tube.
The administration of oral PGE2 was associated with sustained loss of viral replication in 47% of chronic hepatitis B patients (Hyman et al., 1999).
As prostaglandin E2 (PGE2) is a natural ligand for all sub-types of the EP receptor, selective effects on one of the sub-types of the EP receptor is impossible to achieve with the endogenous prostaglandins.
Several prostanoid receptors and modulators of those receptors have been reported with different range of selectivity for the various receptor subtypes (Coleman et al. 1994, Abramowitz et al., 2000; Benoit et al., 2002).
Recently, EP2 agonists have been developed (U.S. Pat. No. 6,235,780 and WO 99/33794). The combination of an EP2 agonist with an EP4 agonist has been developed as combined treatment for osteoporosis (US 20010056060). EP4 selective agonists have been developed for the treatment of bone disorders (WO 02/42268 and WO 01/46140), erectile dysfunction (WO 99/02164) and other prostaglandin related disorders (WO 02/24647, US 20020004495, WO 00/03980). EP2 and EP4 antagonists have been also reported (Benoit et al., 2002).
It would be desirable to develop new compounds and methods of treatment of diseases and disorders associated with the prostaglandin family, notably EP2 and/or EP4 receptors sub-types.